1. Field of the Invention
This invention relates to a system for removing gas bubbles from a flow channel in a microfluidic device.
2. Discussion of the Art
Microfluidic devices are designed to carry out analytical processes in a limited space, i.e., small reaction chambers and flow channels. In a sealed microfluidic device, the formation of gas bubbles in the flow channels is inevitable on account of such operational steps as mixing, dilution, separation, and other steps. In general, gas bubbles are removed from solutions by incorporating vent holes in a conduit to allow gas to escape. Gas bubbles in microfluidic devices occur when the flow channels of the devices are not fully primed. Gas bubbles are formed when plugs of liquid collide during a mixing step. Gas bubbles are formed by electrolysis of water around electrodes when the flow of liquid is driven by electrokinetic forces. The presence of gas bubbles adversely affects the precision of the rate of flow. The presence of gas bubbles also adversely affects the mixing of liquids. Gas bubbles act as an insulating layer for electrokinetic pumping.
Gas bubbles often interfere with optical measurements, if optical detection is required. Optical signals cannot differentiate a gas from a liquid. The presence of gas bubbles in flow channels makes it difficult to determine accurate quantities of reagents for chemical reactions. If chemical reactions are called for, reaction kinetics cannot be controlled on account of the uncertainty of the volume of gas and interference caused by the presence of gas bubbles. For liquids having a high surface tension, such as, for example, water, gas bubbles present an obstacle to flow in a flow channel. Liquids containing gas bubbles are less likely to wet the walls of the flow channel and flow in the microfluidic device.
For the foregoing reasons, trapped or dissolved gases should be removed from flow channels for microfluidic analysis.
U.S. Pat. No. 6,326,211 discloses a miniaturized integrated nucleic acid diagnostic device and system. The device is capable of performing one or more sample acquisition and preparation operations, in combination with one or more sample analysis operations. For example, the device can integrate several or all of the operations involved in sample acquisition and storage, sample preparation and sample analysis, within a single integrated unit. The device can be used in nucleic acid based diagnostic applications and de novo sequencing operations. However, the device and system described herein cannot control the timing of an actual chemical reaction subsequent to the mixing step. The patent is concerned only with mixing and does not consider reactions of chemicals and detection of the reaction product.
U.S. Pat. No. 6,811,752 discloses a device comprising a plurality of microchambers having a closed vented environment, wherein each microchamber is in operative communication with a filling port and a vent aperture. The device further comprises a base which is sandwiched between two liquid-impermeable membranes, with at leas one of the membranes being gas permeable. This reference also discloses a method for introducing a fluid into a plurality of microchambers of the device, wherein each filling port is aligned with a pipette tip, and the fluid is introduced into and through the filling port. The fluid then flows along a fluid flow groove providing fluid flow communication between the filling port and the microchamber, and into the microchamber. However, the device requires external pumps and valves. The patent does not disclose microchannels and removal of localized gas bubbles, nor does the patent disclose detection of gas bubbles to control reaction kinetics.
U.S. Pat. No. 6,615,856 discloses a method of controlling fluid flow within a microfluidic circuit using external valves and pumps connected to the circuit. The external valves and pumps, which are not part of the microfluidic substrate, control fluid pumping pressure and the displacement of air out of the fluid circuit as fluid enters into the circuit. If a valve is closed, air cannot be displaced out of circuit, which creates a pneumatic barrier that prevents fluid from advancing within the circuit (under normal operating pressures). However, the device requires external pumps and valves.
U.S. Pat. No. 6,409,832 discloses a device for promoting protein crystal growth (PCG) using flow channels of a microfluidic device. A protein sample and a solvent solution are combined within a flow channel of a microfluidic device having laminar flow characteristics which forms diffusion zones, providing for a well defined crystallization. Protein crystals can then be harvested from the device. However, the device requires external pumps and valves.
U.S. Pat. No. 6,415,821 discloses magnetically actuated fluid handling devices using magnetic fluid to move one or more fluids through microsized flow channels. Fluid handling devices include micropumps and microvalves. Magnetically actuated slugs of magnetic fluid are moved within microchannels of a microfluidic device to facilitate valving and/or pumping of fluids and no separate pump is required. The magnets used to control fluid movement can be either individual magnets moved along the flow channels or one or more arrays of magnets whose elements can be individually controlled to hold or move a magnetic slug. Fluid handling devices include those having an array of electromagnets positioned along a flow channel which are turned on and off in a predetermined pattern to move magnetic fluid slugs in desired paths in the flow channel. However, the device requires external pumps and valves. The patent does not mention hydrophobic membranes, nor does it mention removal of gas bubbles. The patent also does not disclose reaction kinetics.
WO 2007001912 discloses a reservoir for use in testing a liquid as part of a microfluidic testing system. The microfluidic testing system includes a testing chamber configured to receive the liquid to be tested. A liquid inlet is fluidly coupled to the testing chamber to allow ingress of the liquid into the testing chamber. A gas outlet is fluidly coupled to the testing chamber to allow egress of gas out of the testing chamber. The gas outlet has an elevation that is higher than the elevation of the liquid inlet such that, as the testing chamber is rotated, the gas is expelled out of the testing chamber through the gas outlet, thereby reducing or preventing a presence of gas bubbles in the liquid. This device does not make use of a hydrophobic membrane to aid in the removal of gas bubbles.
EP 1671700 discloses a method of controlling environmental conditions within a fluidic system, e.g., preventing bubble formation, where such environmental conditions can affect the operation of the system in its desired function. Such environmental conditions are generally directed to the fluids themselves, the movement of such fluids through these systems, and the interaction of these fluids with other components of the system, e.g., other fluids or solid components of the system. This system does not use a vent or a hydrophobic membrane to remove gas bubbles during the process.
Microfluidic devices exhibit numerous advantages as compared with devices having conventional flow channels. Microfluidic devices dramatically reduce the quantities of reagents and samples, thereby resulting in lowered costs. Microfluidic devices reduce the quantities of hazardous materials, e.g., biohazardous materials and organic solvents. Microfluidic devices require a smaller amount of floor space than do conventional analyzers. Microfluidic devices enable integration of various unit operations, such as, for example, separation, mixing, reacting, and detecting. Microfluidic devices enable assays to be carried out in a lesser amount of time, as compared with the time required by conventional diagnostic analyzers. Microfluidic devices can be automated with little difficulty, thereby enhancing consistency and reproducibility of test results.
Detection of gas bubbles is required because access to and control of the chemical reaction or kinetics as reactants pass through the system is difficult. Detection of gas bubbles enables controlling the commencement of mixing, reacting, and detecting in assays where determination of the concentration of an analyte is based on the measurements related to certain rates, such as, for example, rates of change in a given parameter. An example of such a parameter is absorbance. See, for example, FIG. 3.1 in AEROSET® Systems Operations Manual, 200154-101-November 2004, page 3-7, incorporated herein by reference.